Mammalian adaptation to extrauterine environment: mitochondrial functional impairment caused by prematurity

Abstract

In this paper we report that, compared with term rat neonates, both mitochondrial content and function are diminished in liver of preterm neonates (delivered 24 h before full term) compromising cellular energy provision in the postnatal period. In addition, there is a parallel reduction in the content of mRNAs encoding mitochondrial proteins in preterm rats. Also, efficient oxidative phosphorylation is not attained in these pups until 3 h after birth. Although isolated liver mitochondria from preterm neonates show a two-fold increase in F1-ATPase beta-subunit and cytochrome c oxidase activity 1 h after birth, the abnormal coupling efficiency between respiration and oxidative phosphorylation (ADP/O ratio) is due to maintenance of high H(+)-leakage values in the inner mitochondrial membrane. Postnatal reduction of the H+ leak occurs concomitantly with an increase in intra-mitochondrial adenine nucleotide concentration. Accumulation of adenine nucleotides in preterm and term liver mitochondria parallels the postnatal increase in total liver adenine nucleotides. Delayed postnatal induction of adenine biosynthesis most likely accounts for the lower adenine nucleotide pool in the liver of preterm neonates. The delayed postnatal accumulation of adenine nucleotides in mitochondria is thus responsible for the impairment in oxidative phosphorylation displayed by organelles of the preterm liver.

Postnatal changes in rhodamine‐123 stained mitochondrial populations are sensitive to protein synthesis inhibitors but mimicked in vitro by atp

“…Thus, liver mitochondria attain the functional capacity of adult life within the first hour after birth as shown by the sharp increase in RCI [ 1,151 and the enhancement in the synthesis of mitochondrial oxidative machinery components [3,16]. In agreement with this our results show (Table 1) that the RCI increased 2-fold within the first hour of extrauterine life, reaching values very similar to those of adult mitochondria.…”

“…In agreement with this our results show (Table 1) that the RCI increased 2-fold within the first hour of extrauterine life, reaching values very similar to those of adult mitochondria. The rapid postnatal enhancement of the RCI and of the ADP/O ratio to adult values suggests that liver mitochondria attain the oxidative phosphorylation capacity of the adult shortly after birth, in agreement with what has been described previously [1, 3,15,16]. Under the same circumstances, the percentages of mitochondria fluorescence populations changed markedly during the first hour of extrauterine life (Table 2).…”

“…mitochondrialfluorescence populations Since protein synthesis is presumably responsible for postnatal mitochondrial differentiation [3], we were prompted to investigate the effect of the inhibition of protein synthesis on postnatal changes in mitochondrial populations. Thus, cycloheximide or streptomycin as cytosolic or mitochondrial protein synthesis inhibitors, respectively, were administered to the newborns immediately after birth and flow cytometry analysis of rhodamine-123~stained mitochondrial populations was carried out 1 h later.…”

“…Fetuses were delivered on 21.5 days of gestation (21.7 days for full gestation) by rapid hysterectomy after cervical dislocation of the mother. To inhibit cytosolic or mitochondrial protein synthesis, newborns were injected immediately after birth with 0.9% NaCl containing 10 mg of cycloheximide/kg body weight or 100 mg streptomycin/kg body weight, respectively [3]. Litter mates were injected with the same volume (50 ~1) of the vehicle.…”

“…Postnatal differentiation of mitochondria is brought about by the synergistic action of two main processes such as the enhancement of the synthesis of protein components of mitochondrial complexes [3] and an increase in the intramitochondrial adenine nucleotide concentrations [ …”